Design of Highly Stabilized β-Hairpin Peptides through Cation−π Interactions of Lysine and <i>N</i>-Methyllysine with an Aromatic Pocket

Riemen, Alexander J.; Waters, Marcey L.

doi:10.1021/bi801706k

Cited by 55 publications

(75 citation statements)

References 32 publications

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“…HB hydrogenbonded site, NHB non-hydrogen-bonded site in PBS, the CD spectra of the designed peptides closely match the CD curves of those fully folded tryptophan zippers in shape and are indicative of well-formed β-hairpin structures (Cochran et al 2001;Dong et al 2006;Takekiyo et al 2009). The minimum at ∼214 nm is consistent with β-sheet structure (Riemen and Waters 2009), and the characteristic maximum at ~228 nm due to the π-π* exciton coupling originating from the interacting Trp residues is indicative of a distinctive cross-strand Trp-Trp interaction ). In the presence of 30 mM SDS, the main spectral features of the peptides do not exhibit any major changes, suggesting that the native conformations are preserved when the molecules interact with lipid bilayers.…”

Section: Peptide Secondary Structure In Different Environmentssupporting

confidence: 59%

Antimicrobial activity and membrane-active mechanism of tryptophan zipper-like β-hairpin antimicrobial peptides

Chou

Wang

et al. 2015

Amino Acids

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Antimicrobial peptides (AMPs) with amphipathic β-hairpin structures have been demonstrated to possess potent antimicrobial activities and great cell selectivities. However, our understanding of β-hairpin antimicrobial peptides lags behind that of α-helices, mainly because it is difficult for short peptides to form robust β-hairpin structures. Tryptophan zipper (trpzip) peptides are among the most stable β-hairpin peptides known to fold spontaneously without requiring covalent disulfide constraint or metal binding. To develop model β-hairpin AMPs with small size and remarkable stability, a series of amphiphilic linear peptides were designed based on the trpzip motif. The sequence of designed peptides is (WK) n (D) PG(KW) n -NH2 (n = 1, 2, 3, 4, 5), and the antimicrobial activity and membrane interaction mechanism of the peptides were evaluated. The results showed that these peptides readily fold into β-hairpin structures in aqueous and membrane-mimicking environments and exhibit broad-spectrum antimicrobial activities against both gram-positive and gram-negative bacteria. The antibacterial potency of the peptides initially increased and then decreased with increasing chain length. WK3, a 14-residue peptide, displayed excellent antimicrobial activity with minimal hemolytic activity and cytotoxicity, suggesting that it possesses great cell selectivity. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), fluorescence spectroscopy, and flow cytometry indicated that representative peptides WK3 and WK4 exert their activities by permeabilizing the microbial membrane and damaging cell membrane integrity. This study reveals the application potential of the designed peptides as promising antimicrobial agents for the control of infectious diseases, and it also provides new insights into the design and optimization of highly stable β-hairpin AMPs with great antimicrobial activities and cell selectivities.

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Section: Peptide Secondary Structure In Different Environmentssupporting

confidence: 59%

Antimicrobial activity and membrane-active mechanism of tryptophan zipper-like β-hairpin antimicrobial peptides

Chou

Wang

et al. 2015

Amino Acids

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“…5–12 They play an important role in the stabilization of secondary structure such as α-helices, 5 and the tertiary structure of peptides such as the TC5b 8 and APP 10, 12 miniproteins. Numerous β-hairpins have been designed to take advantage the aromatic-aromatic (Ar-Ar) interactions, 13–17 cation-π interactions, 16–18 and CH-π interactions. 16, 17 …”

Section: Introductionmentioning

confidence: 99%

VCD spectroscopic properties of the β‐hairpin forming miniprotein CLN025 in various solvents

2010

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Electronic and vibrational circular dichroism are often used to determine the secondary structure of proteins, because each secondary structure has a unique spectrum. In order to determine these spectral features, polypeptides that are known to adopt a particular conformation along their entire length are studied ideally. Little is known about the vibrational circular dichroic spectroscopic features of the β-hairpin. In this study, the VCD spectral features of a decapeptide, YYDPETGTWY (CLN025), which forms a stable β-hairpin that is stabilized by intramolecular weakly polar interactions and hydrogen bonds were determined. Molecular Dynamics simulations and ECD spectropolarimetry were used to confirm that CLN025 adopts a β-hairpin in water, TFE, MeOH and DMSO and to examine differences in the secondary structure, hydrogen bonds and weakly polar interactions. CLN025 was synthesized by microwave-assisted solid phase peptide synthesis with Nα-Fmoc protected amino acids. The VCD spectra displayed a (−,+,−) pattern with bands at 1640 to 1656 cm−1, 1667 to 1687 cm−1 and 1679 to 1686 cm−1 formed by the overlap of a lower frequency negative couplet and a higher frequency positive couplet. A maximum IR absorbance was observed at 1647 to 1663 cm−1 with component bands at 1630 cm−1, 1646 cm−1, 1658 cm−1 and 1675 to 1680 cm−1 that are indicative of the β-sheet, random meander, either random meander or loop and turn, respectively. These results are similar to the results of others, who examined the VCD spectra of β-hairpins formed by DPro-Xxx turns and indicate that observed pattern is typical of β-hairpins.

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“…With the exception of cyclization, mutations at terminal sites have yielded only modest changes in hairpin stability; terminal coulombic effects (ΔΔG U ¼ 1.5-2.5 kJ∕mol) standing as the only generally observed capping effect (11,18,19). Pi-cation interactions have also been shown to provide significant hairpin stabilization (20), but instances in which the interaction appears near the ends of hairpins have provided only marginal stability increases (18,(21)(22)(23)). An unnatural π-cation interaction has also been shown to stabilize the turn in a tripeptide (24).…”

mentioning

confidence: 99%

Stabilizing capping motif for β-hairpins and sheets

Kier

Shu²,

Eidenschink³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

158

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Although much has been learned about the design of models of β-sheets during the last decade, modest fold stabilities in water and terminal fraying remain a feature of most β-hairpin peptides. In the case of hairpin capping, nature did not provide guidance for solving the problem. Some observations from prior turn capping designs, with further optimization, have provided a generally applicable, "unnatural" beta cap motif (alkanoyl-Trp at the N terminus and Trp-Thr-Gly at the C terminus) that provides a net contribution of 6 þ kJ∕mol to β-hairpin stability, surpassing all other interactions that stabilize β-hairpins including the covalent disulfide bond. The motif, made up entirely of natural residues, is specific to the termini of antiparallel β-strands and reduces fraying at the ends of hairpins and other β-sheet models. Utilizing this motif, 10-to 22-residue peptide scaffolds of defined stereochemistry that are greater than 98% folded in water have been prepared. The β-cap can also be used to staple together short antiparallel β-strands connected by a long flexible loop.beta sheets | capping stabilization | peptide hairpins | Trp/Trp interactions C apping motifs are well-known features of protein and peptide secondary structure; specifically, terminal alpha helix caps (especially N caps) are common both in proteins and designed peptides (1-4). The basis for helix capping is straightforward: countering the helix macrodipole and providing additional H-bonding interactions (1). Caps increase the fold population of isolated α-helical peptides and have been a boon to the design of α-helix models. β-Structures have capping requirements wholly different from those of helices; the ends of canonical β-sheets and hairpins do not have dipole moments or unsatisfied H bonds.The a priori design of model β-sheet systems (5), focused on hairpins, has lagged behind that of α-helix counterparts. The key discoveries that improved β-hairpin stabilities outside of protein contexts have been sequences with good turn propensities, for example D-Pro-Gly (pG) (6), heterochiral pP (7), and Aib-Gly (8) [or less favorably, Asn-Gly (NG) (5, 9)] and the incorporation of optimized cross-strand pairings [most notably Trp/Trp pairs flanking the turn (10-14)]. However, longer hairpin models are typically still frayed at the termini; to date, fully folded spectroscopic reference values have only been attained via cyclization (15-17). With the exception of cyclization, mutations at terminal sites have yielded only modest changes in hairpin stability; terminal coulombic effects (ΔΔG U ¼ 1.5-2.5 kJ∕mol) standing as the only generally observed capping effect (11,18,19). Pi-cation interactions have also been shown to provide significant hairpin stabilization (20), but instances in which the interaction appears near the ends of hairpins have provided only marginal stability increases (18,(21)(22)(23)). An unnatural π-cation interaction has also been shown to stabilize the turn in a tripeptide (24). There has been limited evidence for hairpin fold sta...

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Design of Highly Stabilized β-Hairpin Peptides through Cation−π Interactions of Lysine and N-Methyllysine with an Aromatic Pocket

Cited by 55 publications

References 32 publications

Antimicrobial activity and membrane-active mechanism of tryptophan zipper-like β-hairpin antimicrobial peptides

Antimicrobial activity and membrane-active mechanism of tryptophan zipper-like β-hairpin antimicrobial peptides

VCD spectroscopic properties of the β‐hairpin forming miniprotein CLN025 in various solvents

Stabilizing capping motif for β-hairpins and sheets

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